Investigations on nicotine-stimulated neuropeptide release from cigarette smoking suggest mechanisms involving positive reinforcement or rewarding processes which might explain the discriminative control of smoking by stimuli dependent of the nicotine-addiction cycle. We shall attempt to demonstrate experimentally, using behavioral markers and biochemical measurements, the contribution of one neuropeptide -- Beta-endorphin -- to the reinforcement of smoking. The basic approach involves a repeated-measures within subjects design, with different experimental conditions studied over successive days and simultaneous measurement of subjective, behavioral, physiological, and biochemical variables. The specific aims of the research are: I) to demonstrate the effects of nicotine intake from smoking on relevant behavioral markers of cholinergic/Beta-endorphinergic activity (cold-water pain and puzzle anxiety); II) to determine whether pain-reduction (antinociception) from smoking is due to the termination of nicotine-withdrawal or to nicotine effects independent of withdrawal; III) to establish whether the frequency or intensity of cigarette smoking is increased by a dysphoric state not associated with the nicotine-addiction cycle, such as anxiety; IV) to sort out the relative contribution of nicotinic cholinergic activity and Beta-endorphinergic activity on pain and anxiety responses through the administration of a cholinergic blocker (mecamylamine), an opiate antagonist (naloxone), or synthetic Beta-endorphin. The project has its long-term research objective the integration of behavioral (psychological) research on nicotine and smoking with biochemical (neuroendocrinological and psychopharmacological) investigations of neuropeptide activity at the normal human level. The health implicatons are that a better understanding of underlying biobehavioral mechanisms in smoking and substance abuse may make possible the development of rational therapies of greater effectiveness than are currently available.